Prehistoric American Indians lived in this region of the fertile Tennessee Valley for many generations. Concentrations of artifacts discovered by archaeologists show evidence of three periods of habitation on the site, the earliest about 5000 years ago.

The first recorded settlers on the land, the John P. Hickman family, came to the site in 1818. At that time, Pond Spring consisted of 1,760 acres. The Hickmans brought with them 56 enslaved African Americans slaves to clear the land, plant cotton, and build several log structures.
In 1827, Col. Benjamin Sherrod purchased Pond Spring and expanded the larger of two log dogtrot houses into a clapboard-covered Federal-style dwelling. The 1818 Hickman cabin and the Sherrod house still stand today.
His grandson, Ben, would marry Daniella Jones in 1859, the daughter of nearby plantation owner, Richard Jones. Ben Sherrod died in 1861 and left Daniella a widow with two small children.

Wheeler, famous for his service as a Confederate General, a U.S. Congressman, and a General in the Spanish-American War, came through Alabama during the Civil War in 1863 after the battle of Chattanooga, Tennessee. He and his cavalry troops rested at the Jones' plantation near Pond Spring after crossing the Tennessee River into Lawrence County.
After the Civil War, Wheeler entered into a three-year courtship with Daniella Sherrod, and they married in 1866 and built a home at Pond Spring. The house, built during the 1870s, is connected to the original Sherrod house by a covered walkway. The 1870s home is the focal point of the 50-acre site which includes 12 buildings, gardens, and archaeological features dating back 5,000 years.
The site gets its name from the large spring-fed pond located onsite.

General Wheeler lived at Pond Spring until his death in 1906, and it remained a large farming operation, with the primary crop being cotton. One of his daughters, Annie Wheeler, served as a Red Cross volunteer nurse in three wars and lived in the house until her death in 1955. After her death, a caretaker who worked for his descendants occupied the site.

In 1994, Wheeler's descendants donated Pond Spring to the state of Alabama and the Alabama Historical Commission. The Joseph Wheeler Plantation was listed in the National Register of Historic Places in 1977.